Involvement of ryanodine receptors in the contraction of small pulmonary veins

The contractile mechanisms involving calcium ions (Ca²⁺) regulation in smooth muscle cells (SMCs) of small intrapulmonary veins (SPVs) are not yet fully understood despite being relevant in lung physiology. Studies on vasoconstriction induced by physiological agonists have not been sufficient to understand the role of ryanodine receptors (RyRs). These calcium channels release Ca²⁺ from the sarcoplasmic reticulum (SR), within the contraction process of SPV. We hypothesize that RyRs act in a stimulus-dependent manner. Here, we first analyzed existing single-cell RNA sequencing datasets of human and rat lungs to evaluate the expression of RyRs in SMC and other cell types, followed by functional studies to assess SPV contraction using an ex vivo precision-cut lung slice (PCLS) model. To understand the participation of RyRs downstream in contraction pathways, different contractile agents were combined with RyRs agonists and antagonists. We demonstrated that RyRs are expressed in lung smooth muscle cells of humans and rats, participating in SPV contraction likely through the Gq-coupled protein receptor pathway.<b>NEW & NOTEWORTHY</b> The results indicate that RyR2 would be the most relevant isoform in SPV contraction induced by depolarization, whereas RyR1 and RyR3 would participate in the contractile mechanism induced by GqPCR agonists. It is worth noting that based on the scRNA seq studies, RyR1 was shown to be the less expressed isoform in SMCs in the rat lung, which indicates that RyR2 and RyR3 may be the most relevant isoforms participating in the contraction of SPV.